ABSTRACT: Triple negative breast cancers (TNBC) have the worst prognoses of human breast cancers. A factor in this poor outcome is the lack of targeted therapies. Major target receptors are absent (ER, PR) or not amplified (HER-2/neu). Cytotoxic chemotherapy persists as the primary systemic treatment option for TNBC patients, and has life-threatening toxicities such bleeding, and kidney and heart damage. Although the recent approval of atezolizumab in combination with nab-paclitaxel is a seminal event, anti-PD-L1 immunotherapy has achieved only modest response rates in TNBC patients. Inhibition of downstream PI3K effectors, such as AKT, has been clinically validated as a treatment modality but therapeutic windows are small. Resistance to AKT inhibitors such as capivasertib has also been observed in TNBC cell lines. Recent studies have shown serum and glucocorticoid-regulated kinase 1 (SGK1) to be a novel target for treatment of TNBC. SGK1 is an anti- apoptotic kinase that drives proliferation and metastasis of TNBC tumors and is not expressed at detectable levels in normal breast tissue. In particular, SGK1 is overexpressed in the Mesenchymal Stem cell-Like (MSL) subtype of TNBC, which accounts for 20% of TNBC tumors. MSL tumors are also classified as claudin-low, and MSL/claudin-low tumors have one of the poorest prognoses among TNBC subtypes for overall survival and metastasis-free survival. Preclinical studies have shown that SGK1 knockdown or pharmacological inhibition of SGK1 (our own preliminary data) impairs proliferation and metastasis of claudin-low TNBC cells. Additional evidence shows that TNBC cells rely on SGK1 to evade death induced by AKT inhibitors. A major difficulty in treating TNBCs arises from the heterogeneity of these tumors, leading to variable treatment outcomes. We hypothesize that dual specificity inhibition of both SGK1 and AKT1 can provide a novel targeted therapy for claudin-low TNBC. Inhibitors of SGK1 previously discovered for other indications are unsuitable for clinical development in combination with AKT inhibitors due to weak cellular potency and inadequate drug-like properties. Using the innovative Leap-to-Lead? technology, we have identified a novel series of dual SGK1/AKT1 inhibitors with cellular potency derived from superior drug-like properties. In this Phase I SBIR, we will optimize the potency, selectivity, and ADME properties of our lead series using structure-guided chemistry (applying our innovative Leap-to-Lead? and BindingSIGHTs design platforms) and a property-driven medicinal chemistry approach. The newly generated analogs will then progress through functional cell assays, kinase selectivity panels, ADME and pharmacokinetic (PK) experiments to select compounds for in vivo evaluation. Finally, we will examine the efficacy of 1-2 lead compounds in a xenograft model of human TNBC. Successful completion of the Phase I SBIR milestones will justify preclinical development of the lead series in Phase II SBIR studies with the goals of optimizing in vivo efficacy in animal models of human TNBC and determining pharmacology and toxicology profiles to select a lead candidate for IND-enabling studies.